CD1d-restricted, invariant natural killer T (iNKT) cells which sense self and microbial lipid antigens are increasingly recognized to play a critical role i inflammatory bowel disease (IBD). The current research proposal addresses the unanswered question of how CD1d functions in specific parenchymal and hematopoietic cells in intestines to regulate iNKT cells and how this information relates to the pathogenesis and treatment of IBD. Our long-term goals are to define the specific CD1d+ cells involved in regulating or promoting iNKT cell- mediated inflammation, how exogenous microbial factors (e.g. Bacteroides fragilis sphingolipids) and endogenous factors (e.g. acid sphingomyelinase regulation of sphingomyelin levels) affect these cell-type associated CD1d functions and acquire new insights into the mechanism(s) by which CD1d mediated IL-10 production affects the capabilities of the intestinal epithelial cell (IEC) barrier through an examination of Paneth cell (PC) function; a CD1d+ IEC subset. The objective of this research is to elucidate how, at both the molecular and physiological levels, CD1d-restricted iNKT cells pathways function in homeostatic and pathologic responses. Our central hypothesis is that specific subsets of CD1d-bearing cells in intestinal tissues and the lipid antigens presented play a critical role in determining the iNKT cel activity and responsiveness to environmental agents that promote or regulate CD1d-restricted intestinal inflammation. This rationale is derived from recent insights demonstrating early life events impact significantly on later life susceptibility to environmental factors that stimulate CD1d-restricted, iNKT cell mediated intestinal inflammation. Our central hypothesis will be tested with four specific aims: 1) Determine which professional CD1d-bearing antigen presenting cell (APC) subset(s) serves a regulatory role in determining iNKT cell responses. 2) Identify the APC subset required for mediating the protective effects elicited by sphingolipids derived from B. fragilis during early life. 3) Determine the role played by sphingomyelin as an endogenous regulator of CD1d-iNKT cell function. 4) Elucidate mechanisms by which IL-10 derived from the IEC protects the barrier.
In Aim 1, we will characterize the role of APC subsets in influencing CD1d-restricted responses and the inflammatory or regulatory behavior of colonic iNKT cells.
Aim 2 will elucidate how early life exposure to B. fragilis-derived glycosphingolipids inhibit iNKT cell expansion and prevent CD1d-restricted inflammatory responses during later life by establishing the APC subset(s) and mechanism(s) involved.
Aim 3 aims to uncover an endogenous pathway that serves to regulate iNKT cell function in later life through ASM mediated degradation of sphingomyelin.
In Aim 4, we seek to understand how CD1d- restricted regulation of IL-10 extends to PC function. Overall, this proposal is significant because it will promote our understanding of how CD1d-restricted, iNKT cell pathways are affected by environmental, genetic and microbial factors and how iNKT cells in turn promote or prevent intestinal inflammation. This research will provide a firm basis upon which to develop a variety of new therapeutic strategies for IBD.

Public Health Relevance

The proposed research is relevant to public health because understanding how CD1d-restricted, invariant natural killer T cell pathways functions in mucosal sites and promotes or prevents intestinal inflammation is critically important to our understanding of inflammatory bowel disease especially in light of recent evidence that these functions are strongly influenced by environmental factors likely to be important to the pathogenesis of this disorder. The proposed studies are relevant to the mission of the NIDDK because they are expected to identify several new therapeutic strategies for inhibiting inflammation associated with inflammatory bowel dis- ease or enhancing immunity in the treatment of cancers and infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK044319-25
Application #
9265443
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
1992-09-30
Project End
2020-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
25
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Iyer, Shankar S; Gensollen, Thomas; Gandhi, Amit et al. (2018) Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses. Cell 173:1123-1134.e11
Aden, Konrad; Tran, Florian; Ito, Go et al. (2018) ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS-STING. J Exp Med 215:2868-2886
Clancy-Thompson, Eleanor; Ali, Lestat; Bruck, Patrick T et al. (2018) IAP Antagonists Enhance Cytokine Production from Mouse and Human iNKT Cells. Cancer Immunol Res 6:25-35
Kim, Walter M; Kaser, Arthur; Blumberg, Richard S (2017) A role for oncostatin M in inflammatory bowel disease. Nat Med 23:535-536
Gensollen, Thomas; Blumberg, Richard S (2017) Correlation between early-life regulation of the immune system by microbiota and allergy development. J Allergy Clin Immunol 139:1084-1091
Schrumpf, Elisabeth; Kummen, Martin; Valestrand, Laura et al. (2017) The gut microbiota contributes to a mouse model of spontaneous bile duct inflammation. J Hepatol 66:382-389
Schrumpf, Elisabeth; Jiang, Xiaojun; Zeissig, Sebastian et al. (2017) The role of natural killer T cells in a mouse model with spontaneous bile duct inflammation. Physiol Rep 5:
Tschurtschenthaler, Markus; Adolph, Timon E; Ashcroft, Jonathan W et al. (2017) Defective ATG16L1-mediated removal of IRE1? drives Crohn's disease-like ileitis. J Exp Med 214:401-422
Kaser, Arthur; Blumberg, Richard S (2017) The road to Crohn's disease. Science 357:976-977
Zeissig, Sebastian; Peuker, Kenneth; Iyer, Shankar et al. (2017) CD1d-Restricted pathways in hepatocytes control local natural killer T cell homeostasis and hepatic inflammation. Proc Natl Acad Sci U S A 114:10449-10454

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